The
European Medicines Agency (EMEA) today recommended contraindicating
Acomplia (rimonabant) from sanofi-aventis, in patients with ongoing
major depression or who are being treated with antidepressants, because
of the risk of psychiatric side effects. Doctors in the EU have already
been warned about this since June 2006 but the Agency’s
Committee for Medicinal Products for Human Use (CHMP) has now
recommended upgrading this warning.

Acomplia has been authorised in the EU since June 2006 as an adjunct to
diet and exercise for the treatment of obese or overweight adult
patients. Psychiatric side effects, in particular depression, were
identified as the main safety issue at the time of approval. They were
reflected in the medicine’s product information as a warning
that doctors should not prescribe Acomplia in patients with
uncontrolled serious psychiatric conditions such as major depression.

In
October 2006, the US FDAissued
Sanofi-Aventis an approvable letter, which is the
bureaucratic equivalent of limbo, or maybe purgatory. It is
half-way between approved and not approved. It means that
more testing is needed before a final decision is made.

In June of this year, the FDA completed a review
(PDF file) of some additional data. A couple of weeks later,
Sanofi-Aventis announced
(PDF file) that they were dropping their application in the USA.
They also noted that they would continue with additional
trials, implying that they have not totally given up on the US market.
Even so, the FDA is concerned about the adverse effect
profile.

Rimonabant has an unusually complex action on a
complex neuronal system.
It acts upon the endocannabinoid system, the same system
affected by cannabis.
Even though it is selective for the CB1 receptors (not having
an effect on CB2 receptors), it affects many different sites in the
brain. Moreover, the effects are not limited to the central
nervous system. It has effects in many peripheral tissues.
Not all of these are known or understood.
Therefore, it has many potential adverse effects.
Because of the complexity and diversity of effects, there is
going to be worry about the possibility of effects that cannot be
predicted, or cannot be uncovered in preclinical trials.

An additional point of interest is that the endocannabinoid
transmitters are retrograde neurotransmitters, that is, the perform
retrograde signaling, from the postsynaptic to the presynaptic
cell.

As you can see, the receptors that rimonabant, and
tetrahydrocannabinol, act upon, are widely
distributed in the brain:

Of course there is a difference between rimonabant and tetrahydrocannabinol (THC).
THC is an agonist, thereby stimulating the neurons that
possess CB1 receptors; rimonabant is an inverse agonist, thereby
actively suppressing neuronal activity.

That slide did not shrink very cleanly, so I will explain.
The top white line on the graph shows the effect upon the
neuron
that an agonist has. The dotted straight line in the middle
shows
the effect of a drug that blocks the receptor, called an antagonist.
An inverse agonist is different. It actively
reduces the
activity of the neuron. To use an analogy, an agonist moves
the
car forward. An antagonist stops the car. An
inverse
agonist puts the car in reverse.

At first that seems like a bad analogy. After all, a neuron
is
either polarized or depolarized, either on or off; there is no middle
setting. In order to understand fully what an inverse agonist
is,
it is necessary to know what effect the receptor has on the inner
workings of the neuron.

Receptors are connected to second messenger systems.
(The
neurotransmitter being the first messenger). The second
messenger
is what signals the cell to let it know that the receptor is occupied.
It does this by facilitating some kind of chemical reaction.

In some situations, the chemical reaction is normally on, to some
extent, when the receptor is not occupied.
This is called constitutive activity.
CB1 receptors normally have some constitutive activity via a
G-protein coupled mechanism. (in fact, the CB1 receptor is
coupled to multiple G-proteins.)

An agonist increases the constitutive
activity; an antagonist leaves it unchanged; an inverse agonist stops
it. Note that some articles do refer to rimonabant as an
antagonist; I have to assume this is either because it sometimes does
act as an antagonist, or the authors are not being precise.

It turns out that CB1 receptors are involved in a wide variety of
functions, having what is called pleiotropic
effects. This is described in this
article:

Although,
the precise mechanisms of action of
rimonabant
have to be further dissected, it is emerging, from both preclinical and
clinical research, that not only is rimonabant an antiobesity drug, but
also its pleiotropic functions affect a broad range of diseases, from
obesity-related comorbidities to drug dependence and cancer…

Starting from the discovery of the endocannabinoid system, a number of
studies have pointed out that altered endocannabinoid signaling and CB1
receptor expression are involved in several pathophysiological
situations, ranging from neurological and psychiatric diseases to
eating, cardiovascular, and reproductive disorders…

Considering the antitumor properties of the cannabinoid receptor
agonists, it could be expected that cannabinoid receptor antagonists,
such as rimonabant, if used alone, would enhance proliferation of
normal and malignant cells, leading to cancer. Some data excluded this
possibility, reporting rather that not only agonists to cannabinoid
receptors but also antagonists, used alone, are able to inhibit cancer
growth (Bifulco et al., 2004) or induce apoptosis in cancer cells
(Derocq et al., 1998; Powles et al., 2005)…

The concerns about the drug expressed at the most recent FDA meeting
about rimonabant are summarized in this
file, which is a powerpoint presentation. (If you
don’t have powerpoint, you still can view it using OpenOffice
or some other viewer.) Some of the illustrations in this post
are from that file.

Concern about malignancy was not documented in that review.
Their main concern was that rimonabant, in animals, had a
narrow therapeutic index. That is, the concentration required
to produce a serious adverse effect was very close to the concentration
required to get a therapeutic effect. The particular adverse
effect they were concerned about was convulsions. They noted
that other CB1 drugs are in development, and they have larger
therapeutic indices.

The FDA committee also was concerned about the potential for rimonabant
to cause or exacerbate depression, possibly including suicidal
thinking. These concerns are quantified and discussed in this
document (PDF file). They report that, from
clinical trial data, the incidence of anxiety was 5.9% ( vs. 2.1% with
placebo); mood alterations with depressive symptoms 4.7% (vs. 2.8%),
and Depressive Disorders 3.9% (vs. 1.7%).

With regard to completed suicides, there was one among 5,262 patients
treated with rimonabant in one study group of patients, and zero in the
2,474 who got placebo. There were four hospitalizations for
depression in the treated patients, one in the placebo group.
Overall, in all studies, there were three completed suicides
in patients exposed to rimonabant. Two of those were in
studies that have not yet been completed, so they were not included in
the first analysis. Although no formal statistical analysis
was presented, those numbers probably are too small to draw any firm
conclusions.

Of greater significance is the finding that occurs when patients with a
prior history of a depressive disorder are examined. Among
those who received placebo, 8.9% developed a depressive disorder during
the trial. Among those who received 20mg rimonabant, 19.1%
developed a depressive disorder.

The panel did not find an increased risk for convulsions, based upon
clinical trial data. However, patients being treated for
epilepsy were excluded from the trials.

That is the consumer to make of all this? The drug is
approved for use in Europe, but not in the USA. Agencies on
both sides of the Atlantic are looking at the same data, but drawing
different conclusions.

This actually is a common circumstance. I can’t cite data,
but it seems that the EU is quicker to approve drugs, and quicker to
pull them from the market. The US is slower to approve drugs,
but more reluctant to pull them once they’ve been approved.

Personally, I think the current EU stance on rimonabant is the correct
one. That is based upon the notion that patients will be
adequately informed of the potential risks, and that the drug will be
prescribed appropriately and its use appropriately monitored.

Comments

Thanks for the excellent backgrounder on rimonabant. It certainly is confusing to consumers when drugs are approved in Europe but not the U.S., and vice versa.

History obviously shows that it pays to be careful with the pharmaceutical weight loss compounds. Earlier offerings have not panned out so well. Nonetheless, it is clear that, through neural mechanisms from dopamine to cannabinoid receptors, diet strongly effects neurotransmission, and the idea of food addictions in addiction-prone people–specifically, carbohydrate-craving obesity as one manifestation of addictive disease–begins to seem quite plausible.

There are no amphetamines. Unfortunately, I do not have any direct knowledge about drug interactions. Plus, various antidepressants have very different patterns of interaction, so it would not be possible to make a blanket statement about that.

The Office of Surgeon General always has been overtly political, a captive Ameritania Hotel New York of the most hysterical public health activists. Its only real powers are tongue-clucking and finger-wagging, usually about the latest moral panic, lecturing the American public to knock off its bad habits, lest somebody get hurt. Richard msn nickleri Carmona’s tenure was no different, which is why it’s laughable to hear him lecture someone else about science.